ZA200410213B

ZA200410213B - Indole derivatives useful as histamine H3 antagonists.

Info

Publication number: ZA200410213B
Application number: ZA200410213A
Authority: ZA
Inventors: Robert G Aslanian; Pietro Mangiaracina; Mwangi W Mutahi; Michael Y Berlin; Kevind D Mccormick; Stuart B Rosenblum
Original assignee: Schering Corp
Priority date: 2002-06-24
Filing date: 2004-12-17
Publication date: 2005-10-20
Also published as: MY135686A; DK1539742T3; AU2003243709B2; CN100497334C; CA2489337C; TW200400031A; ATE344798T1; JP4326468B2; CN1662524A; HK1072259A1; US6951871B2; AU2003243709A1; NZ537200A; KR20050009757A; CY1105986T1; EP1539742A1; MXPA05000193A; DE60309598T2; WO2004000831A1; DE60309598D1

Description

INDOLE DERIVATIVES USEFUL AS HISTAMINE H; ANTAGONISTS

FIELD OF THE INVENTION

The present invention relates to novel substituted indoles and derivatives thereof, useful as histamine H; antagonists. The invention also relates to pharmaceutical compositions comprising said compounds and their use in treating inflammatory diseases, allergic conditions and central nervous system disorders. The invention also relates to the use of a combination of novel histamine Hs antagonists of this invention with histamine Hy compounds for the treatment of inflammatory diseases and allergic conditions, as well as pharmaceutical compositions comprising a combination of one or more novel histamine Hz antagonist compounds of the invention with one or more histamine H; compounds.

BACKGROUND OF THE INVENTION

The histamine receptors, Hy, H, and Hj are well-identified forms. The Hj receptors are those that mediate the response antagonized by conventional antihistamines. H, receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals. Through H, receptor- mediated responses, histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.

Hs receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under . control of the sympathetic nervous system. Specifically, Hs receptor activation by histamine attenuates nonepinephrine outflow to resistance and capacitance vessels, causing vasodilation.

Imidazole H3 receptor antagonists are well known in the art. Mare recently, . non-imidazole Hz receptor antagonists have been disclosed in PCT US01/32151, filed October 15, 2001, and US Application 10/095,134, filed March 11, 2002. ’ US 5,869,479 discloses compositions for the treatment of the symptoms of allergic rhinitis using a combination of at least one histamine H1 receptor antagonist and at least one histamine H3 receptor antagonist.

SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula I: ilk oe rR g \ I A R?

Ny MA A Ny N—_" n Pp or a pharmaceutically acceptable salt or solvate thereof, wherein: ais 0 to 3; bis 0to 3; nis1,2or3; pis1,2or3, ris0, 1,2, or3;

Xis a bond or C4-Cg alkylene;

M*is CH or N;

M? is C(R®) or N; with the provisos that when M? is N, p is not 1; and that when ris 0, M? is

C(R%; and that the sum of p and ris 1 to 4;

Y is —C(=0)-, -C(=S)-, -(CH2)q-, -NR*C(=0)-, -C(=0)NR*-, -C(=0)CHy-, -SO1.5-, —C(=N-CN)-NH- or —-NH-C(=N-CN)-; with the provisos that when M'is N, Y is not ~NR*C(=0)- or -NH-C(=N-CN)-; and when M?is N, Y is not -C(=0)NR*- or : —C(=N-CN)-NH-; qis 1 to 5, provided that when M' and M? are both N, gis not 1;

Zis a bond, C4-Cs alkylene, C,-Cg alkenylene, -C(=0)-, -CH(CN)- or —CH,C(=0)NR*-;

R'is .

R R R R R ys sa S R—¢~ N=9 ps @) @ WAR 0)

CS Cl ) R AN au An pos QR’ oy QR @) © \& (R®)z (R®) > (RP); or (RE), ;

Q is -N(R®- , -S- or -O-: kis 0, 1,2, 3 or4; k1is0, 1, 2 or 3; k2is 0, 1 or 2; the dotted line represents an optional double bond:

R and R’ are independently selected from the group consisting of H, C4-Cg alkyl, halo(C+-Cg)alkyl-, C4-Cg alkoxy, (C4-Ce)alkoxy-(C+-Cg)alkyl-, (C1-Ce)-alkoxy- (C4-Ce)alkoxy, (C+-Ce)alkoxy-(C+-Ce)alkyl-SOq.o, R*-aryl(C4-C)alkoxy-, R*aryl- (C1-Ce)alkyl-, R**-aryl, R®-aryloxy, R¥-heteroaryl, (Cs-Ce)cycloalkyl, (Ca-Ce)cycloalkyl- (C1-Ce)alkyl, (C-Cs)cycloalkyl-(C1-Ce)alkoxy, (Cs-Cs)cycloalkyl-oxy-, R¥-heterocyclo- alkyl, N(R*)(R*'}-(C4-Ce)alkyl-, -N(R*®)(R"), -NH-(C1-Co)alkyl-O-(C1-Co)alkyl,” -NHC(O)NH(R?®); R%-S(0)o.-, halo(C1-Cs)alkyl-S(O)o.o-, N(R**)(R%")-(C+-Cg)alkyl- 8(Oo2-, benzoyl, (C-Cs)alkoxy-carbonyl, R¥-heterocycloalkyl-N(R%)-C(O)-, (C-

Ce)alkyl-N(R*)-C(O)-, (C1-Cs)alkyl-N(C1-Cs alkoxy)-C(O)-, —C(=NOR*)R*® and —NHC(0)R?; and when the optional double bond is not present, R’ can be OH:

R® is H, C4-Cs alkyl, halo(C4-Cs)alkyl-, (C1-Cs)alkoxy-(Co-Ce)alkyl-, R*-aryl(C;-

Ce)alkyl-, R*-aryl, R®-heteroaryl, R*2-heteroaryl(Cs-Cg)alkyl-, (C3s-Cs)cycloalkyl, (Ca- © 20 Cecycloalkyl-(Cs-Ce)alkyl, R¥-heterocycloalkyl, R¥-heterocycloalkyl(C1-Cs)alkyl,

N(R¥)(R*)-(Cz-Cg)alkyl-, R?-S(0)-, halo(C+-Cs)alkyl-S(O).-, R?-S(O)o.1-(Co-Ce)alkyl-, halo(C1-Ce)alkyl-S(O)o.1-(C2-Cs)alkyl-, (C1-Ce)alkyl-N(R*)-SO,-, or R*%-heteroaryl-SO,;

R? is a six-membered heteroaryl ring having 1 or 2 heteroatoms independently selected from N or N-O, with the remaining ring atoms being carbon; a five-

membered heteroaryl ring having 1, 2, 3 or 4 heteroatoms independently selected . from N, O or S, with the remaining ring atoms being carbon; R*-quinolyl; R*2.aryl;

Ny—N (Lp hid ; or heterocycloalkyl; wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R®;

R®is H, halogen, C+-Cs alkyl, -OH or (C1-Cg)alkoxy;

R* is independently selected from the group consisting of hydrogen, C4-Cs alkyl, Ca-Cs cycloalkyl, (Cs-Cg)cycloalkyl(C1-Cg)alkyl, R*-aryl, R**-aryl(C;-Cg)alkyl, and

R*heteroaryl;

R® is hydrogen, C4-Cg alkyl, -C(O)R?, -C(O),R®, ~C(O)N(R®),, R**-aryl(C;-

Cs)alkyl or (C4-Cg)alkyl-SO,-;

R® is 1 to 3 substituents independently selected from the group consisting of -OH, halogen, C4-Cs alkyl, C4-Cs alkoxy, -CF3, -NR*R°, -(C1-Cg)alkyl-NR*R®, phenyl,

R*_phenyl, NO,, -CO2R*, -CON(R*),, -NHC(O)N(R*)2, R*-heteroaryl-SO,-NH-, R*-aryl-(C-Cg)alkyl-NH-, R*-heteroaryl-(C1-Cs)alkyl-NH-, R*-heteroaryl-

NH-C(0)-NH-, R¥-heterocycloalkyl-N(R*)-C(0)- and R*-heterocycloalkyl-

N(R®)-C(O)-NH-;

R'? is independently selected from the group consisting of C4-Cs alkyl, hydroxyl, C4-Ce alkoxy, or fluoro, provided that when R%is hydroxy or fluoro, then R" is not bound to a carbon adjacent to a nitrogen; or R' forms a C; to C; alkyl bridge from one ring carbon to another ring carbon;

R" is independently selected from the group consisting of C4-Cs alkyl, hydroxyl, C1-Cs alkoxy, or fluoro, provided that when R' is hydroxy or fluoro then R" is not bound to a carbon adjacent to a nitrogen; or forms a C4 to C, alkyl bridge from one ring carbon to another ring carbon; or R¥is =0; ] R? is independently selected from the group consisting of hydrogen, C1-Cg alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups . independently selected from halogen, -CF3, -OCF3, hydroxyl, or methoxy; or when two

R? groups are present, said two R? groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring;

R? is C;-Cg alkyl, R*-aryl or heterocycloalkyl;

R* is H, C4-Cs alkyl, -SO,R* or R*-ary!;

R* is independently selected from the group consisting of C+-Cs_alkyl, halogen,

CN, —CF3, -OH, C4-Cs alkoxy, (C4-Cg)alkyl-C(O)-, aryl-C(0)-, N(R*)(R?)-C(O)-,

N(R*)(R®)-S(0)1.2-, halo-(C4-Ce)alkyl- or halo-(C;-Cg)alkoxy-(C4-Ce)alkyl-;

R? is H, C4-Cs alkyl, Ray or R®-aryl(C1-Ce)alkyl-:

R¥ is H, C4-Cs alkyl-, R®-aryl or R®-aryl(C4-Ce)alkyl-:

R*'is H, C4-Cs alkyl-, R®-aryl, R*-aryl(Cs-Ce)alkyl-, (C+-Ce)alkyl-C(O)-, R®-aryl-

C(0)-, N(R*)(R®)-C(O)-, (C+-Cs)alkyl-S(O),- or R*-aryl-S(0),-: or R®* and R*" together are -(CHz)a.s-, —(CHz)2-O-(CHa)o- or ~(CH2)2-N(R*)-(CHa),- and form a ring with the nitrogen to which they are attached:

R* is 1 to 3 substituents independently selected from the group consisting of

H. -OH, halogen, C1-Cs alkyl, C+-Cg alkoxy, R*-aryl-O-, -SR?, -CF3, -OCF3, -OCHF,, -NRR®, phenyl, R®-phenyl, -NO,, -CO,R*, -CON(R*),, -S(0),R%, -S(0)oN(R®),, -N(R*)S(0);R?, -CN, hydroxy-(C-Ce)alkyl-, -OCH,CH,0R?, and R¥-aryl(C1-Ce)- alkyl-O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens;

R*is 1 to 3 substituents independently selected from the group consisting of

C1-Ce alkyl, halogen, -CN, -NO,, -OCHF; and —O-(C+-Cg)alkyl;

R* is 1 to 3 substituents independently selected from the group consisting of

H, halogen, -CF3, -OCF3, -OH and —OCHs.

R* is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, C1-Cs alkyl, hydroxy, C4-Cg alkoxy, phenoxy, -CF3, -N(R%),, -COORZ and -NOg;

R*is independently selected from the group consisting of H and C;-Cg alkyt; and

R¥ is independently selected from the group consisting of H, C4-Cs alkyl and (C1-Ce)alkoxycarbonyl.

This invention also provides a pharmaceutical composition comprising an i effective amount of at least one compound of formula | and a pharmaceutically acceptable carrier.

This invention further provides a method of treating: allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the GI tract, hyper- and hypo- motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders

(e.g., hypersomnia, somnolence, and narcolepsy), disturbances of the central nervous system, attention deficit hyperactivity disorder (ADHD), hypo- and hyperactivity of the central nervous system (for example, agitation and depression), . and/or other CNS disorders (such as Alzheimer’s, schizophrenia, and migraine) comprising administering to a patient in need of such treatment an effective amount of at least one compound of formula I. “Patient” means a mammal, typically a human, although veterinary use is also contemplated.

Compounds of this invention are particularly useful for treating allergy, allergy- induced airway responses and/or congestion.

This invention further provides a pharmaceutical composition comprising an effective amount of a combination of at least one compound of formula | and at least one Hy receptor antagonist in combination with a pharmaceutically acceptable carrier.

This invention further provides a method of treating allergy, allergy-induced airway (e.g., upper airway) responses, and/or congestion (e.g., nasal congestion) comprising administering to a patient in need of such treatment (e.g., a mammal, such as a human being) an effective amount of a combination of at least one compound of formula | and at least one H, receptor antagonist.

Kits comprising a compound of formula | in a pharmaceutical composition, and a separate Hq receptor antagonist in a pharmaceutical composition in a single package are also contemplated.

DETAILED DESCRIPTION OF THE INVENTION

Preferred definitions of the variables in the structure of formula | are as follows:

R'is preferably 3-indolyl or 1-indolyl. The double bond is preferably present in the R' substituent.

Ris preferably H, alkyl, R*2.aryl, R*-heteroaryl, (C4-Cg)alkoxy-carbonyl or (C1-Co)alkyl-N(R*)-C(0)-. When R is (C+-Ce)alkyl-N(R?)-C(0)-, RZ is preferably H or

C1-Cs alkyl. More preferably, R is R*-aryl or R*-heteroaryl. Especially preferred are ) R*-phenyl and R*2-pyridyl. Ris preferably H.

R® is preferably H, R*-aryl(C1-Cs)alkyl-, R¥*heteroaryl(C1-Ce)alkyl-, R*2.anyl,

R*-heteroaryl, (C4-Cg)alkyl-N(R?®)-SO,- or R*¥-heterocycloalkyl(C1-Cg)alkyl-.

Especially preferred are H, R**-benzyl, R*2-pyridylmethyl, (C4-Ce)alkyl-N(R?*)-SO,- wherein R? is H or C;-Cs alkyl, and piperidinoethyl.

R® is preferably H, halogen or —-CF3z and kis 0 or 1. When R'is.an aza- or diaza derivative of indole, R is preferably as defined above, and k; and k» are preferably zero. . X is preferably a bond.

R%is preferably a six-membered heteroaryl ring, optionally substituted with one - substituent. More preferably, R? is pyridyl, pyrimidyl or pyridazinyl, optionally substituted with -NH,.

Y is preferably —-C(O)-.

Z is preferably straight or branched C+-C; alkyl. Methylene is an especially preferred Z group.

Mis preferably N; ais preferably 0; and n is preferably 2; the optional double bond in the ring containing M’ is preferably not present (i.e., a single bond is present).

M? is preferably C(R% wherein R® is hydrogen or fluoro; b is preferably 0; ris preferably 1; and p is preferably 2.

As used herein, the following terms have the following meanings, unless indicated otherwise: alkyl (including, for example, the alkyl portions of arylalkyl and alkoxy) represents straight and branched carbon chains and contains from one to six carbon atoms; alkylene represents a divalent straight or branched alkyl chain, e.g., ethylene (-CH2-) or propylene (—CHCH,CH,-); haloalkyl or haloalkoxy represent alkyl or alkoxy chains as defined above wherein one or more hydrogen atoms are replaced by halogen atoms, e.g., -CFs3, CF3CH2CH,-, CF3CF,- or CF30-; aryl (including the aryl portion of arylalkyl) represents a carbocyclic group containing from 6 to 15 carbon atoms and having at least one aromatic ring (e.g., aryl ] is a phenyl or naphthyl ring), with all available substitutable carbon atoms of the carbocyclic group being intended as possible points of attachment; . 30 arylalkyl represents an aryl group, as defined above, bound to an alkyl group, as defined above, wherein said alkyl group is bound to the compound; cycloalkyl represents saturated carbocyclic rings of from 3 to 6 carbon atoms; halogen (halo) represents fluoro, chloro, bromo and iodo:

heteroaryl represents cyclic groups, having 1 to 4 heteroatoms selected from } O, Sor N, said heteroatom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the . aromatic heterocyclic groups preferably containing from 2 to 14 carbon atoms. The rings do not contain adjacent oxygen and/or sulfur atoms. Examples include but are not limited to isothiazolyl, isoxazolyl, oxazolyl, furazanyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furanyl (furyl), pyrrolyl, pyrazolyl, pyranyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridyl (e.g., 2-, 3-, or 4-pyridyl), pyridyl N-oxide (e.g., 2-, 3-, or 4-pyridyl N-oxide), triazinyl, pteridinyl, indolyl (benzopyrrolyl), pyridopyrazinyl, isoquinolinyl, quinolinyl, naphthyridinyl; the 5- and 6-membered heteroaryl groups included in the definition of

R? are exemplified by the heteroaryl groups listed above; all available substitutable carbon and nitrogen atoms can be substituted as defined. heterocycloalkyl represents a saturated, carbocylic ring containing from 3 to carbon atoms, preferably from 4 to 6 carbon atoms, which carbocyclic ring is 15 interrupted by 1 to 3 hetero atoms selected from -O-, -S-, -SO-, -SO, or -NR*- wherein R* represents H, C4 to Ce alkyl, arylalkyl, -C(O)R?, -C(O)OR®, or -C(O)N(R®), (wherein each R? is independently selected); examples include but are not limited to 2- or 3-tetrahydrofuranyl, 2- or 3- tetrahydrothienyl, 2-, 3- or 4- piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperizinyl, 2- or 4-dioxanyl, 1,3-dioxolanyt, 1,3,5-trithianyl, pentamethylene sulfide, perhydroisoquinolinyl, decahydroquinolinyl, trimethylene oxide, azetidinyl, 1-azacycloheptanyl, 1,3-dithianyl, 1,3,5-trioxanyl, morpholinyl, thiomorpholinyl, 1,4-thioxanyl, and 1,3,5-hexahydrotriazinyl, thiazolidinyl, tetrahydropyranyl. ©) , for example in the structure

R

RO—~ N= represents a nitrogen atom that is located at one of the 4 non-fused positions of the ring, i.e., positions 4, 5, 6 or 7 indicated below:

-9g-

R -

A

RS rd NS 56

Similarly, @) means that two nitrogen atoms are located at any two of the 4 non-fused positions of the ring, e.g., the 4 and 6 positions, the 4 and 7 positions, or the 5 and 6 positions.

A dotted line in the structure of formula | or in the structures defining R' indicates an option double bond. The presence or absence of a double bond in the structure of formula | is independent of the presence or absence of a double bond in the R substituent.

Also, as used herein, “upper airway” usually means the upper respiratory system--i.e., the nose, throat, and associated structures.

Also, as used herein, “effective amount” generally means a therapeutically effective amount.

A line drawn into a ring means that the indicated bond may be attached to any of the substitutable ring carbon atoms.

Certain compounds of the invention may exist in different isomeric (e.g., enantiomers, diastereoisomers and geometric) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms and tautomers are also included.

The compounds of this invention are ligands for the histamine Hj receptor.

The compounds of this invention can also be described as antagonists of the Hj receptor, or as Hz antagonists.

The compounds of the invention are basic and form pharmaceutically ) acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, } 25 malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms can differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the . salts are otherwise equivalent to their corresponding free base forms for purposes of this invention. —- Depending upon the substituents on the inventive compounds, one may be able to form salts with bases. Thus, for example, if there is a carboxylic acid substituent in the molecule, a salt may be formed with an inorganic as well as organic base such as, for example, NaOH, KOH, NH,OH, tetraalkylammonium hydroxide, and the like.

The compounds of formula | can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydrate. in general, the solvated form, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated form for purposes of the invention.

The compounds of this invention can be combined with an H4 receptor antagonist (i.e., the compounds of this invention can be combined with an H; receptor antagonist in a pharmaceutical composition, or the compounds of this invention can be administered with an Hq receptor antagonist).

Numerous chemical substances are known to have histamine H4 receptor antagonist activity and can therefore be used in the methods of this invention. Many

H+ receptor antagonists useful in the methods of this invention can be classified as ethanolamines, ethylenediamines, alkylamines, phenothiazines or piperidines.

Representative H4 receptor antagonists include, without limitation: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, ; levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, : 30 temelastine, trimeprazine and triprolidine. Other compounds can readily be evaluated to determine activity at Hq receptors by known methods, including specific blockade of the contractile response to histamine of isolated guinea pig ileum. See for example,

WO98/06394 published February 19, 1998.

Claims

WHAT IS CLAIMED 1S: ;

1. A compound represented by the structural formula . (R'?), R"), a a UE RN SAN n p or a pharmaceutically acceptable salt or solvate thereof, wherein: ais 0 to 3; bis 0 to 3; nis1,2or3; pis1,2or3; ris0, 1,2, or 3; X is a bond or C¢-Cg alkylene; M'is CH or N; M? is C(R%) or N; with the provisos that when M? is N, p is not 1; and that when ris 0, M? is C(R%); and that the sum of p and ris 1 to 4; Y is =C(=0)-, -C(=S)-, -(CHa)q -, -NR*C(=0)-, -C(=0)NR*-, -C(=O)CH-, -SO1.o- , =C(=N-CN)-NH- or ~NH-C(=N-CN)-; with the provisos that when M' is N, Y is not —NR*C(=0)- or -NH-C(=N-CN)-; and when M2 is N, Y is not -C(=O)NR*- or —C(=N-CN)-NH-; qis 1 to 5, provided that when M' and M? are both N, gis not 1; Z is a bond, C4-Cg alkylene, C-Cg alkenylene, -C(=0)-, -CH(CN)- or —CH,C(=0)NR*-; R'is R R R R R ; a S os aN 3 REP N= pis { Wy @ $Y RA ®G ®, RYT meg

Q is -N(R%- , -S- or —O-;

kis 0,1, 2, 3 or4;

k1is 0,1, 2 or 3;

k2 is 0,1 or 2;

the dotted line represents an optional double bond;

R and R’ are independently selected from the group consisting of H, C1-Cs alkyl, halo(C4-Ce)alkyl-, C4-Cs alkoxy, (C1-Cg)alkoxy-(C+-Cs)alkyl-, (C4-Ce)-alkoxy- (C4-Cs)alkoxy, (C1-Cs)alkoxy-(C1-Ce)alkyl-SOq.2, R¥-aryl(C4-Cg)alkoxy-, R*%-aryl-

(C+-Ce)alkyl-, R*-aryl, R¥-aryloxy, R*-heteroaryl, (Cs-Cs)cycloalkyl, (Cs-Ce)cycloalkyl- (C4-Ce)alkyl, (Ca-Ce)cycloalkyl-(C4-Cg)alkoxy, (C3-Cs)cycloalkyl-oxy-, R¥-heterocyclo- alkyl, N(R*)(R*")~(C+-Cg)alkyl-, -N(R**)(R*"), -NH-(C4-Cg)alkyl-O-(C4-Cs)alkyl, -NHC(O)NH(R®); R?-S(0)o.2-, halo(C1-Cs)alkyl-S(O)o.2-, N(R¥)(R*')-(C4-Ce)alkyl- S(0)o.2-, benzoyl, (C4-Cg)alkoxy-carbonyl, R¥-heterocycloalkyl-N(R?%)-C(O)-, (Cs-

Ce)alkyl-N(R®)-C(O)-, (C1-Ce)alkyl-N(C+-Cg alkoxy)-C(O)-, -C(=NOR*)R*® and ~NHC(O)R?; and when the optional double bond is not present, R’ can be OH;

R® is H, C1-Cs alkyl, halo(C+-Ce)alkyl-, (Ci-Cs)alkoxy-(C2-Ce)alkyl-, R*-aryl(Cs- Ce)alkyl-, R*-aryl, R*-heteroaryl, R*-heteroaryl(C:-Cg)alkyl-, (C3-Ce)cycloalkyl, (Ca- Ce)cycloalkyl-(C+-Ce)alkyl, R¥-heterocycloalkyl, R¥-heterocycloalkyl(Cs-Cg)alkyl,

N(R*)(R*)-(Cx-Ce)alkyl-, R?2-S(O),-, halo(C1-Cs)alkyl-S(O)z-, R?2-S(0)p.1-(C2-Ce)alkyl-, halo(C1-Cg)alkyl-S(O)o.1-(C2-Cs)alkyl-, (C1-Ce)alkyl-N(R**)-SO,-, or R*-heteroaryl-SO;

membered heteroaryl ring having 1, 2, 3 or 4 heteroatoms independently selected from N, O or §, with the remaining ring atoms being carbon; R¥*-quinolyt; R¥*-aryl;

NaN (Ly bd ; or heterocycloalkyl, wherein said six-membered heteroaryl ring or said five-membered heteroaryl ring is optionally substituted by R®;

R®is H, halogen, C1-Cs alkyl, -OH or (C4-Cg)alkoxy; . R* is independently selected from the group consisting of hydrogen, C4-Cs alkyl, C3-Cs cycloalkyl, (Ca-Ce)cycloalkyl(C1-Cg)alkyl, R*-aryl, R*-aryl(C,-Cg)alkyl, and . R3*2-heteroaryl; R® is hydrogen, C4-Cs alkyl, -C(O)R%, -C(0);R?®, =C(O)N(R®),, R*-aryI(C;- Cs)alky! or (C4-Ce)alkyl-SO,-; R®is 1 to 3 substituents independently selected from the group consisting of -OH, halogen, C4-Cs alkyl, C4-Cg alkoxy, -CF3, -NR*R®, -(C4-Cs)alkyl-NR*R®, phenyl, R*-phenyl, NO, -CO2R*, -CON(R*),, -NHC(O)N(R*),, R*-heteroaryl-SO»-NH-, R*-aryl-(Cs-Ce)alkyl-NH-, R%-heteroaryl-(C1-Cs)alkyl-NH-, R¥-heteroaryl- NH-C(O)-NH-, R¥-heterocycloalkyl-N(R?°)-C(O)- and R¥ -heterocycloalkyl- N(R%)-C(O)-NH-; R'? is independently selected from the group consisting of C+-Cs alkyl, hydroxyl, C1-Ce alkoxy, or fluoro, provided that when Ris hydroxy or fluoro, then R'? is not bound to a carbon adjacent to a nitrogen; or R' forms a Cto C» alkyl bridge from one ring carbon to another ring carbon; R" is independently selected from the group consisting of C4-Cg alkyl, hydroxyl, C1-Cs alkoxy, or fluoro, provided that when R*? is hydroxy or fluoro then R" is not bound to a carbon adjacent to a nitrogen; or forms a C4 to C, alkyl bridge from one ring carbon to another ring carbon; or R™ is =O; Ris independently selected from the group consisting of hydrogen, C4-Cg alkyl, or aryl, wherein said aryl group is optionally substituted with from 1 to 3 groups independently selected from halogen, -CF3;, -OCF3, hydroxyl, or methoxy; or when two R? groups are present, said two R?® groups taken together with the nitrogen to which they are bound can form a five or six membered heterocyclic ring; R? is C1-Cs alkyl, R*-aryl or heterocycloalkyl; R** is H, C4-Cs alkyl, -SO,R? or R*-aryl;

. R* is independently selected from the group consisting of C4-Cg alkyl, halogen, CN, —CF3, -OH, C4-Cs alkoxy, (C1-Ce)alkyl-C(O)-, aryl-C(0)-, N(R*)(R’)-C(O)-, : 30 N(R*R®)-S(0)i.2-, halo-(C4-Ce)alkyl- or halo-(C+-Cs)alkoxy-(C4-Ceg)alkyl-; R? is H, C4-Cg alkyl, R*-aryl or R®-aryl(C;-Cg)alkyl-; R* is H, C;-Cs alkyl-, R*®-aryl or R®-aryl(C;-Cg)alkyl-; R'is H, C-Cs alkyl-, R®-aryl, R®-aryl(C1-Cg)alkyl-, (C1-Cs)alkyl-C(O)-, R*-aryl- C(O), N(R*)(R®)-C(O)-, (C1-Ce)alkyl-S(O),- or R*-aryl-S(0)y-;

or R* and R*! together are -(CHa)s.5-, —(CH2)2-O~(CHa)p- of —(CHa2)2-N(R?®)-(CH,),- and form a ring with the nitrogen to which they are attached; R* is 1 to 3 substituents independently selected from the group consisting of ) H, -OH, halogen, C-Cs alkyl, C-Cs alkoxy, R®-aryl-O-, -SR%, -CF5, -OCF3, -OCHF», -NR*R®, phenyl, R¥-phenyl, -NO,, -CO,R*, -CON(R*)2, -S(0),R%, -S(O),N(R®),, -N(R*)S(0):R?, -CN, hydroxy-(C+-Cs)alkyl-, -OCH2CH,0R%, and R*>-aryl(C;-Cs)- alkyl-O-, wherein said aryl group is optionally substituted with 1 to 3 independently selected halogens; R* is 1 to 3 substituents independently selected from the group consisting of C4-Cg alkyl, halogen, -CN, -NO,, -OCHF; and —O-(C4-Cg)alkyl; R* is 1 to 3 substituents independently selected from the group consisting of H, halogen, -CF3, -OCF3, -OH and —OCHj. R¥ is 1 to 3 substituents independently selected from the group consisting of hydrogen, halo, C4-Cs alkyl, hydroxy, C4-Cg alkoxy, phenoxy, -CFs, -N(R*®),, -COORZ and —NOy; R* is independently selected from the group consisting of H and C4-Cs alkyl; and RY is independently selected from the group consisting of H, C4-Ce alkyl and (C4-Ce)alkoxycarbonyl.

2. A compound of claim 1 wherein M'is N, ais 0, n is 2, and the optional double bond in the ring containing M' is not present.

3. A compound of claim 1 wherein M? is C(R®) wherein R® is hydrogen or halogen, bis 0; ris1and pis 2.

4. A compound of claim 1 wherein Y is —C(O)-. 20 5S.

A compound of claim 1 wherein Z is straight or branched C4-C; alkyl.

6. A compound of claim 1 wherein R? is a six-membered heteroaryl ring, : optionally substituted with one R® substituent.

7. A compound of claim 1 wherein R'is

R R . gas as \, / \V REO my

8. A compound of claim 7 wherein Ris H, alkyl, R*-aryi, R*.heteroaryl, (C4-Ce)alkoxy-carbonyl or (C4-Cg)alkyl-N(R*®)-C(O)-.

9. A compound of claim 8 wherein R is R*.pheny! or R32-pyridyl.

10. A compound of claim 7 wherein R’ is hydrogen; R®is H, R*-aryl(C;-Cs)alkyl-, R¥-heteroaryl(C+-Ce)alkyl-, R¥-aryl, R®-heteroaryl, (C;-Cs)alkyl-N(R®)-SO,- or R¥'- heterocycloalkyl(C+-Ce)alkyl-; R® is H, halogen or —CF3;; and kis 0 or 1.

11. A compound of claim 10 wherein R® is H, R*-benzyl, R**-pyridyimethyl, piperidinoethyl or (C4-Cg)alkyl-N(R?®)-SO,- wherein R% is H or C4-Cs alkyl.

12. A compound of claim 1 selected from the group consisting of compounds of the formula Oo R ~N AN ~~ R25 wherein R, R®, R® and R? are as defined in the table: Ror] RS] OR QC) (CH3)2N-SO,- H Joi =; 7 NH, n/N NH, CH3CH»-0-C(O)- H H J FON, : CH3-NH-C(0)- H H JO =, Z NH, Ng H H SN \ 7 = ji NH;

PCT/US2003/019619 \_7 aa I | $ Nn JO uy; NH, —N $ H Ny_NH; CO or ny

13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically effective carrier.

14. The use of a compound of claim 1 for the preparation of a medicament for the treatment of allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer’s disease, schizophrenia, and migraine.

15. A pharmaceutical composition comprising an effective amount of a compound of claim 1, and an effective amount of Hy receptor antagonist, and a pharmaceutically effective carrier.

16. The use of a compound of claim 1 for the preparation of a medicament for use in combination with an Hy receptor antagonist for treating allergy, allergy-induced airway responses, and congestion.

17. The use of a compound of claim 1 and an H, receptor antagonist for the preparation of a medicament for treating allergy, allergy-induced airway responses, and congestion.

18. The use of claim 16 or claim 17 wherein said H, receptor antagonist is : selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, AMENDED SHEET

PCT/US2003/019619 carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.

19. A substance or composition for use in a method for the treatment of allergy, allergy-induced airway responses, congestion, hypotension, cardiovascular disease, diseases of the Gl tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, obesity, sleeping disorders, disturbances of the central nervous system, attention deficit hyperactivity disorder, hypo and hyperactivity of the central nervous system, Alzheimer's disease, schizophrenia, and migraine, said substance or composition comprising a compound of claim 1, and said method comprising administering said - : substance or composition.

20. A substance or composition for use in a method for treating allergy, allergy-induced airway responses, and congestion, said substance or composition comprising a compound of claim 1 and an H, receptor antagonist, and said method comprising administering said substance or composition.

21. A substance or composition for use with an H, receptor antagonist in a method for treating allergy, allergy-induced airway responses, and congestion, said substance or composition comprising a compound of claim 1, and said method comprising administering said substance or composition and said H, receptor antagonist.

22. A substance or composition for use in a method of treatment of claim 20 or claim 21 wherein said H, receptor antagonist is selected from: astemizole, azatadine, azelastine, acrivastine, brompheniramine, cetirizine, chlorpheniramine, clemastine, cyclizine, carebastine, cyproheptadine, carbinoxamine, descarboethoxyloratadine, diphenhydramine, doxylamine, AMENDED SHEET

) PCT/US2003/019619 dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, loratadine, levocabastine, meclizine, mizolastine, mequitazine, mianserin, noberastine, norastemizole, picumast, pyrilamine, promethazine, terfenadine, tripelennamine, temelastine, trimeprazine or triprolidine.

23. A compound according to any one of claims 1 to 12, substantially as herein described and illustrated.

24. A composition according to claim 13 or claim 15, substantially as herein described and illustrated.

25. Use according to any one of claims 14 or 16 to 18, substantially as herein described and illustrated.

26. A substance or composition for use in a method of treatment according to any one of claims 19 to 22, substantially as herein described and illustrated.

27. A new compound, a new composition, a new use of a compound as claimed in claim 1 and an H, receptor antagonist, a new use of a compound as claimed in claim 1, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET